Fatty Acid Synthase:Molecular Target for Breast Cancer Therapy & Chemoprevention

脂肪酸合成酶：乳腺癌治疗的分子靶点

基本信息

批准号：
8295514
负责人：
RUTH LUPU
金额：
$ 46.12万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-16 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8295514
关键词：
Abbreviations Acetyl Coenzyme A Acetylcysteine Address Adipose tissue Adjuvant Apoptosis Apoptotic Biochemical Genetics Breast Breast Cancer Cell Breast Cancer Treatment Breast Carcinoma Cancer Patient Carcinoma Carnitine Palmitoyltransferase I Cell Death Cells Cerulenin Clinic Clinical Clinical Trials Conduct Clinical Trials Cysteine Data Development Disease Disease-Free Survival Down-Regulation ERBB2 gene Effectiveness Enzymes Epidermal Growth Factor Receptor Epigallocatechin Gallate Esters Estrogen Antagonists Estrogen Receptor Modulators Estrogen receptor positive Event Family member Fatty Acids Fatty-acid synthase Figs - dietary Fluorouracil Foundations Funding Generations Genes Goals Grant Growth Heregulin Human Immunohistochemistry In Vitro Laboratories Lead Link Liver MAPK14 gene MAPK8 gene Maintenance Malonyl Coenzyme A Mediating Membrane Lipids Membrane Potentials Metabolic Metastatic to Mitochondria Molecular Molecular Target NADP National Surgical Adjuvant Breast and Bowel Project Natural History Neoadjuvant Therapy Noninfiltrating Intraductal Carcinoma Normal Cell North Central Cancer Treatment Group Noxae Paclitaxel Palmitates Pathogenesis Pathway interactions Patients Pharmacotherapy Phenotype Play Population Production Progesterone Receptors Proliferating Protein Family Proteins Publishing Puma Reactive Oxygen Species Resistance Risk Role Sphingolipids Stress Tamoxifen Taxane Compound Therapeutic Tissues Transcriptional Activation Translating Trastuzumab Treatment Failure Up-Regulation Xenograft Model base cancer cell cancer chemoprevention cancer therapy cell growth chemotherapy clinically relevant cytochrome c cytochrome c(3)cytotoxicity design effective therapy gallocatechol high risk hormone therapy in vivo inhibitor/antagonist inorganic phosphate insight long chain fatty acid major outer membrane protein malignant breast neoplasm mitochondrial membrane novel novel therapeutics outcome forecast overexpression preclinical study prevent research study response response marker sphingosine 1-phosphate taxane theranostics therapeutic target treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Fatty Acid Synthase (FASN) is an enzyme that catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA in cells. Normal cells (except liver and adipose tissue) have low levels of FASN activity. In rapidly proliferating cancer cells fatty acids can be synthesized de novo to provide lipids for membrane formation. Our general hypothesis is that FASN is a promising therapeutic target for invasive breast carcinomas. FASN is highly expressed in invasive breast and other carcinomas, and is prominent in higher grade tumors correlating with poor prognosis. Our data shows that 60% of invasive breast carcinomas express high levels of FASN and FASN expression is a marker for poor prognosis and poor disease free survival. Interestingly, FASN is highly coexpressed with the three breast cancer histopathological groups: Estrogen Receptor positive (ER+), HER2 3+ overexpressing (HER2+) and triple negative (TN) [which do not express ER, Progesterone Receptor (PgR), and HER2+). Our preliminary studies show that pharmacological inhibition of FASN in breast cancer synergizes with chemotherapeutical agents such as Taxol, and with antiestrogens and trastuzumab targeted therapies increasing growth inhibition and apoptotic cell death in vitro and in vivo. We demonstrated that blockage of FASN inhibits tumor growth and induces apoptosis, triggering deteriorating effects which lead to apoptotic cell death including: i inhibition of palmitate, hence the inhibition of sphingolipids synthesis; ii) mitochondria damage and release of Cyt c; iii) increase Reactive Oxygen Species (ROS) generation; and iv) upregulation of BH3-only family proteins (Noxa, Bim, Puma). In this proposal we will extend these concepts using a variety of biochemical, genetic and therapeutic approaches: First, we will examine the clinical value of FASN as a theranostic (predictive) marker for response to targeted therapy in breast-cancer patients, in adjuvant and neoadjuvant setting. Second, we will assess the role of: i) BH3-only proteins Noxa, Bim and Puma in FASN inhibition induced apoptosis: ii) the synergistic effect of inhibitors of FASN and Taxol induced apoptosis; iii) the lnk between FASN inhibition and increased ROS production and BH3-only protein upregulation. Last, we will perform preclinical studies to assess a newly develop anti-FASN agent in combination with antiestrogens, Trastuzumab and Taxol. This proposal will provide new insight into the action of FASN inhibitors and the information needed to translate our findings into the clinic. Our goal is to develop novel rationally designed therapeutic approaches for breast cancer. PUBLIC HEALTH RELEVANCE: This application responds to the urgent need to develop strategies to predict response to cancer treatments. The characterization of Fatty Acid Synthase as a molecular event accompanying the pathogenesis and natural history of breast cancer disease will help determine its clinical relevance to metastatic breast cancer patients and will help in the development of effective treatment strategies.

描述（由申请人提供）：脂肪酸合酶（FASN）是一种酶，可催化细胞中乙酰基-COA和malonyl-COA的长链脂肪酸从头合成。正常细胞（肝脏和脂肪组织除外）具有较低的FASN活性。在快速增殖的癌细胞中，可以从头合成脂肪酸，以提供膜形成的脂质。我们的总体假设是，FASN是侵入性乳腺癌的有前途的治疗靶标。 FASN在浸润性乳房和其他癌中高度表达，并且在与预后不良相关的高级肿瘤中很突出。我们的数据表明，有60％的侵入性乳腺癌表达高水平的FASN和FASN表达是预后不良和无疾病生存不良的标志。有趣的是，FASN与三个乳腺癌组织病理学组高度同时表达：雌激素受体阳性（ER+），HER2 3+过表达（HER2+）和三位阴性（TN）[不表达ER，孕酮受体（PGR）和HER2+）。我们的初步研究表明，乳腺癌中FASN的药理抑制作用与化学治疗剂（如紫杉醇）协同作用，以及抗雌激素和曲妥珠单抗靶向疗法，可增加生长抑制和体外和体内凋亡细胞死亡。我们证明FASN的阻塞抑制肿瘤的生长并诱导凋亡，引发恶化的作用，导致凋亡细胞死亡，包括：I抑制棕榈酸酯，因此抑制了鞘脂的合成； ii）线粒体损伤和Cyt C的释放； iii）增加活性氧（ROS）的产生；和iv）仅BH3家庭蛋白（NOXA，BIM，PUMA）上调。在此提案中，我们将使用多种生化，遗传和治疗方法扩展这些概念：首先，我们将研究FASN作为疗法（预测）标志物的临床价值，以应对乳腺癌患者的靶向治疗，辅助和新辅助治疗。其次，我们将评估以下原因的作用：i）仅BH3蛋白NOXA，BIM和PUMA在FASN抑制作用诱导的凋亡中的作用：ii）FASN和紫杉醇诱导的凋亡抑制剂的协同作用； iii）FASN抑制与ROS产生增加和仅BH3蛋白上调之间的LNK。最后，我们将进行临床前研究，以评估新开发的抗FASN剂与抗雌激素，曲妥珠单抗和紫杉醇结合使用。该建议将为FASN抑制剂的作用以及将我们的发现转化为诊所所需的信息提供新的见解。我们的目标是为乳腺癌开发新颖的理性设计的治疗方法。公共卫生相关性：此应用程序响应迫切需要制定策略来预测对癌症治疗的反应。脂肪酸合酶作为伴随乳腺癌疾病的发病机理和自然病史的分子事件的表征将有助于确定其与转移性乳腺癌患者的临床相关性，并有助于制定有效的治疗策略。